Monolithic intravaginal rings comprising progesterone and methods of making and uses thereof

ABSTRACT

The present invention relates to monolithic intravaginal rings comprising progesterone, methods of making, and uses thereof. The intravaginal rings comprise progesterone, a polysiloxane elastomer, and a pharmaceutically acceptable hydrocarbon or glycerol esters of a fatty acid.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application is a continuation of U.S. application Ser. No.14/045,311, filed Oct. 3, 2013, (now U.S. Pat. No. 10,548,904), which isa continuation of U.S. application Ser. No. 12/364,990, filed Feb. 3,2009 (now U.S. Pat. No. 8,580,293), which claims priority to U.S.Provisional Application No. 61/026,115, filed Feb. 4, 2008, and U.S.Provisional Application No. 61/139,454, filed Dec. 19, 2008, each ofwhich is hereby incorporated by reference in its entirety.

This application claims benefit of the filing dates of U.S. Appl. No.61/026,115, filed Feb. 4, 2008, and U.S. Appl. No. 61/139,454, filedDec. 19, 2008, each of which is hereby incorporated by reference in itsentirety.

FIELD OF THE INVENTION

The present invention relates to monolithic intravaginal ringscomprising progesterone, methods of making, and uses thereof. Theintravaginal rings comprise progesterone, a polysiloxane elastomer, anda pharmaceutically acceptable hydrocarbon or glycerol esters of a fattyacid.

BACKGROUND OF THE INVENTION

Progesterone is a C-21 steroid hormone and belongs to a class ofhormones called progestogens. It is the major naturally occurringsteroid and is a precursor in the biosynthesis of other steroids,particularly glucocorticoids, androgens and estrogens.

Progesterone stimulates the growth of the uterus and also stimulates anumber of specific changes in the endometrium and myometrium.Progesterone is essential for the development of decidual tissue and thedifferentiation of luminal and glandular epithelial tissue. It alsoplays several roles in gestation, including breast enlargement,inhibition of uterine contractility, maintenance of gestation,immunological protection of the embryo, and inhibition of prostaglandinsynthesis.

Progesterone has been used in the treatment of a number of clinicaldisorders such as luteal phase defects, dysfunctional uterine bleeding,endometriosis, endometrial carcinoma, benign breast disease,pre-eclampsia, and regimens of in vitro fertilization. The luteal phaseof a natural cycle is characterized by the formation of a corpus luteum,which secretes steroid hormones, including progesterone. Afterfertilization and implantation, the developing blastocyst secretes humanchorionic gonadotropin (“hCG”), which maintains the corpus luteum andits secretions. Normal luteal function is essential for maintainingpregnancy and data suggest that progesterone is necessary for themaintenance of early pregnancy. Penzias, A. S., Fertility and Sterility77:318-323 (2002).

Unfortunately, not all women of reproductive age are able to becomepregnant, or maintain a pregnancy; indeed, about twelve to fifteenpercent of women of reproductive age in the United States have receivedan infertility service at some time in their lives. AssistedReproductive Technology (“ART”) generally involves the surgical removalof eggs from a woman's ovaries, fertilizing them with sperm in thelaboratory, and then returning them to either the donor woman's oranother woman's uterus (Centers for Disease Control, AssistedReproductive Technology Success Rates, National Summary and FertilityClinic Reports. U.S. Department of Health and Human Services, 2004).There are three types of ART: (a) IVF (in vitro fertilization) involvesextracting the eggs, fertilizing them in the laboratory, andtransferring resulting embryos to the uterus through the cervix, (b)GIFT (gamete intrafallopian transfer) involves placing unfertilized eggsand sperm into the woman's fallopian tubes using a laparoscope throughan abdominal incision, and (c) ZIFT (zygote intrafallopian transfer)involves extracting the eggs, fertilizing them in the laboratory, andusing a laparoscope to place the fertilized egg(s) into a woman'sfallopian tubes.

ART is also further classified by whether a woman's own eggs were used(nondonor), or eggs were donated from another woman (donor). Inaddition, the embryos used can be newly fertilized (fresh), orpreviously fertilized, frozen, and then thawed (frozen). For many women,in conjunction with ART, steps must be taken to prime the uterus forimplantation, and to sustain the pregnancy after implantation. Therehave been many tools developed to aid in this process.

In the mid-1980s, gonadotrophin releasing hormone (“GnRH”) agonists wereincorporated into ovarian stimulation regimens and are associated withimproved outcomes after IVF and other assisted reproductivetechnologies. GnRH agonists work by suppressing the pituitary andpreventing premature surges of endogenous luteinizing hormone (“LH”)during IVF cycles, allowing time for a larger number of oocytes to reachmaturity prior to harvesting as well as increasing follicular growth.However, GnRH agonists inhibit the corpora lutea in these cycles and maycreate an iatrogenic luteal phase defect.

Use of a GnRH agonist causes suppression of pituitary LH secretion foras long as 10 days after the last dose and pituitary function may notreturn completely until 2-3 weeks after the end of therapy. Without thisLH signal, the corpus luteum may be dysfunctional, and subsequentprogesterone and estrogen secretion may be abnormal, compromisingendometrial receptivity, and potentially leading to decreasedimplantation and pregnancy rates. Pritts et al., Human Reproduction17:2287-2299 (2002).

Various hormones, including estrogens, progesterone, and hCG, have beenused during the luteal phase and beyond in IVF cycles for luteal phasesupport. A 1994 meta-analysis showed that the use of hCG or progesteroneled to significantly higher pregnancy rates than placebo. Soliman etal., Fertility and Sterility 61:1068-76 (1994). Progesterone in numerousforms (oral, vaginal, intramuscular (“IM”)) is considered to be theagent of choice because hCG is associated with a higher risk of ovarianhyperstimulation syndrome (“OHSS”), a potentially life-threateningcondition associated with an increased risk of thromboembolism.

Most treatment protocols advocate the use of progesterone throughout thefirst trimester of pregnancy, since corpus luteum activity has beendemonstrated up to week 10 of pregnancy, although progesteronesupplementation continuing beyond a positive serum pregnancy test maynot be needed. The goal of progesterone supplementation is therefore toassist a corpus luteum that may have become compromised during ovulationinduction or oocyte retrieval.

Oral, IM, and intravaginal progesterone preparations are available. Oralformulations appear to be inferior for luteal support. Serumprogesterone levels are highest with IM administration, but because ofthe uterine first pass effect with IM administration, vaginaladministration results in higher endometrial progesterone levels.Bulletti et al., Human Reproduction 12:1073-9 (1997).

IM progesterone (50-100 mg daily) is widely used, but requires dailyinjections and is painful, uncomfortable, and inconvenient for patients;some patients may even develop a sterile abscess or an allergic responseto the oil vehicle. Toner J. P., Human Reproduction 15 Supp. 1:166-71(2000). Vaginal progesterone gel (Crinone®/Prochieve® 8%; ColumbiaLaboratories, Livingston, N.J.) is less painful and easier to use thanIM, but also requires daily dosing, may be messy, and due to potentialleakage, may not provide a full dose with every application. Crinone® isa bioadhesive vaginal gel containing micronized progesterone in anemulsion system. The carrier vehicle is an oil in water emulsioncontaining the water swellable, but insoluble, polymer polycarbophil.

The use of a progesterone vaginal insert (Endometrin®) 3 times daily hasrecently been approved by the U.S. Food and Drug Administration (“FDA”)to support embryo implantation and early pregnancy by supplementation ofcorpus luteal function as part of an ART treatment program for infertilewomen. In addition, vaginal use multiple times daily of micronizedprogesterone capsules has been reported and is used clinically, butluteal phase supplementation or replacement is not an FDA-approvedindication for this product.

There is also published information comparing a vaginal progesteronering to IM progesterone for use in both IVF and oocyte donation.Zegers-Hochschild et al., Human Reproduction 15:2093-2097 (2000).

Intravaginal devices for delivering progesterone and/or intravaginaldevices comprising polysiloxane elastomers are discussed in U.S. Pat.Nos. 3,545,439; 3,948,262; 4,012,496; 5,869,081; 6,103,256; 6,056,976;and 6,063,395.

BRIEF SUMMARY OF THE INVENTION

The present invention is directed to a method for treating a lutealphase defect in a patient in need thereof, the method comprisingadministering to the patient a monolithic intravaginal ring comprising(a) a therapeutically effective amount of progesterone, (b) apolysiloxane elastomer, and (c) a pharmaceutically acceptablehydrocarbon or glycerol esters of a fatty acid, wherein the polysiloxaneelastomer is present in a concentration of about 55% to about 90% bytotal weight of the ring.

The present invention is directed to a method for treating a lutealphase defect in a patient in need thereof, the method comprisingadministering to the patient a monolithic intravaginal ring comprising(a) a therapeutically effective amount of progesterone, (b) apolysiloxane elastomer, and (c) a pharmaceutically acceptable oil,wherein the polysiloxane elastomer is present in a concentration ofabout 55% to about 90% by total weight of the ring.

The present invention is directed to a monolithic intravaginal ring fortreating a luteal phase defect in a patient in need thereof, the ringcomprising (a) about 5% to about 40% by weight of progesterone, (b)about 55% to about 90% by weight of polysiloxane elastomer, and (c)about 0.1% to about 10% by weight of a pharmaceutically acceptablehydrocarbon or glycerol esters of a fatty acid, wherein the progesteroneis homogeneously dispersed in the elastomer.

The present invention is directed to a monolithic intravaginal ring fortreating a luteal phase defect in a patient in need thereof, the ringcomprising (a) about 5% to about 40% by weight of progesterone, (b)about 55% to about 90% by weight of polysiloxane elastomer, and (c)about 0.1% to about 10% by weight of a pharmaceutically acceptable oil,wherein the progesterone is homogeneously dispersed in the elastomer.

The present invention is directed to a process for making a monolithicintravaginal ring, the process comprising (a) mixing progesterone, apharmaceutically acceptable hydrocarbon or glycerol esters of a fattyacid, and a polysiloxane to form a homogeneous mixture, (b) placing thehomogeneous mixture into a mold, and (c) curing the mold at about 60° C.to about 180° C., wherein the polysiloxane is present in a concentrationof about 55% to about 90% by total weight of the ring.

The present invention is directed to a process for making a monolithicintravaginal ring, the process comprising (a) mixing progesterone, apharmaceutically acceptable oil, and a polysiloxane to form ahomogeneous mixture, and (b) placing the homogeneous mixture into amold, wherein the polysiloxane is present in a concentration of about55% to about 90% by total weight of the ring.

The present invention is directed to a method for treating a lutealphase defect in a patient in need thereof, the method comprisingadministering to a patient a monolithic intravaginal ring comprising (a)progesterone, (b) a dimethylpolysiloxane elastomer, and (c) apharmaceutically acceptable hydrocarbon or glycerol esters of a fattyacid, wherein the ratio of progesterone to elastomer is about 1:1 toabout 1:10, the progesterone is homogeneously dispersed in theelastomer, the ratio of progesterone to hydrocarbon or glycerol estersof a fatty acid is about 1:0.1 to about 1:100, and wherein theprogesterone is released from the monolithic intravaginal ring for up toabout 18 days after administration to the patient.

The present invention is directed to a method for treating a lutealphase defect in a patient in need thereof, the method comprisingadministering to a patient a monolithic intravaginal ring comprising (a)progesterone, (b) a dimethylpolysiloxane elastomer, and (c) apharmaceutically acceptable oil, in a ratio of about 4:15:1,respectively, wherein the progesterone is homogeneously dispersed in theelastomer, and wherein the progesterone is released from the monolithicintravaginal ring for up to about 18 days after administration to thepatient.

The present invention is directed to a method for treating a lutealphase defect in a patient in need thereof, the method comprisingadministering to the patient a monolithic intravaginal ring comprising(a) about 15% to about 25% by weight of progesterone, (b) about 70% toabout 80% by weight of a dimethylpolysiloxane elastomer, and (c) about1% to about 10% by weight of a pharmaceutically acceptable hydrocarbonor glycerol esters of a fatty acid, wherein the progesterone ishomogeneously dispersed in the elastomer, and wherein the progesteroneis released from the monolithic intravaginal ring for up to about 18days after administration to the patient.

The present invention is directed to a method for treating a lutealphase defect in a patient in need thereof, the method comprisingadministering to the patient a monolithic intravaginal ring comprising(a) about 15% to about 25% by weight of progesterone, (b) about 70% toabout 80% by weight of a dimethylpolysiloxane elastomer, and (c) about1% to about 10% by weight of a pharmaceutically acceptable oil, whereinthe progesterone is homogeneously dispersed in the elastomer, andwherein the progesterone is released from the monolithic intravaginalring for up to about 18 days after administration to the patient.

The present invention is directed to a method for treating a lutealphase defect in a patient in need thereof, the method comprisingadministering to the patient a monolithic intravaginal ring comprising(a) progesterone, (b) a dimethylpolysiloxane elastomer, and (c) mineraloil, in a ratio of about 4:15:1, respectively, wherein the progesteroneis homogeneously dispersed in the elastomer, and released from theintravaginal ring at about 15 mg/day to about 25 mg/day in vivo andwherein the intravaginal ring is replaced after about every 7 daysfollowing administration to the patient.

The present invention is directed to a method for treating a lutealphase defect in a patient in need thereof, the method comprisingadministering to the patient a monolithic intravaginal ring comprising(a) about 20% progesterone, (b) about 75% MED-4840, and (c) about 5%mineral oil, wherein the progesterone is homogeneously dispersed in theelastomer, and released from the intravaginal ring at about 15 mg/day toabout 25 mg/day in vivo and wherein the intravaginal ring is replacedafter about every 7 days following administration to the patient.

In some embodiments, the progesterone is homogeneously dispersed in thepolysiloxane elastomer.

In some embodiments, the polysiloxane elastomer is adiorganopolysiloxane elastomer. The diorganopolysiloxane elastomer canbe a dimethylpolysiloxane elastomer. The dimethylpolysiloxane elastomercan further comprise a dimethylmethylhydrogen polysiloxane crosslink.

In some embodiments, the pharmaceutically acceptable hydrocarbon orglycerol esters of a fatty acid is present in a concentration of about0.1% to about 10% by total weight of the ring.

In some embodiments, the pharmaceutically acceptable hydrocarbon orglycerol esters of a fatty acid is selected from mineral oil, siliconeoil and combinations thereof. In some embodiments, the pharmaceuticallyacceptable hydrocarbon or glycerol esters of a fatty acid is mineraloil.

In some embodiments, the progesterone is present in a concentration ofabout 15% to about 30% by total weight of the ring.

In some embodiments, the progesterone is released at a steady rate forabout 1 day to about 14 days. In some embodiments, the progesterone isreleased at a steady rate for about 1 day to about 10 days. In someembodiments, the progesterone is released at a steady rate for about 1day to about 7 days.

In some embodiments, the progesterone is released from the monolithicintravaginal ring at a steady rate for up to about 10 days afteradministration to the patient. In some embodiments, the progesterone isreleased from the monolithic intravaginal ring at a steady rate for upto about 14 days after administration to the patient. In someembodiments, the progesterone is released from the monolithicintravaginal ring at a steady rate for up to about 18 days afteradministration to the patient.

In some embodiments, the polysiloxane is vinyl end blocked. In someembodiments, the polysiloxane is dimethylpolysiloxane.

In some embodiments, the process further comprises mixing a secondpolysiloxane into the homogeneous mixture prior to placing into themold. In some embodiments, the second polysiloxane is a crosslinker. Insome embodiments, the crosslinker is dimethylmethylhydrogenpolysiloxane.

In some embodiments, the placing of the homogeneous mixture is byinjection.

In some embodiments, the progesterone is released from the intravaginalring at about 10 mg/day to about 40 mg/day in vivo. In some embodiments,the progesterone is released from the intravaginal ring at about 10mg/day to about 30 mg/day in vivo. In some embodiments, the progesteroneis released from the intravaginal ring at about 15 mg/day to about 25mg/day in vivo.

In some embodiments, the intravaginal ring is replaced after about 14days following administration to the patient. In some embodiments, theintravaginal ring is replaced after about 7 days followingadministration to the patient.

BRIEF DESCRIPTION OF THE FIGURES

FIG. 1 depicts a top-down view of a monolithic intravaginal ring of thepresent invention.

FIG. 2 depicts a process flow chart representing a process for preparingmonolithic intravaginal rings of the present invention.

FIG. 3 shows a comparison of the mean serum estradiol levels in apatient following administration of a progesterone intravaginal ring ofthe present invention or a progesterone vaginal gel.

FIG. 4 shows a comparison of the mean serum progesterone levels in apatient following administration of a progesterone intravaginal ring ofthe present invention or a progesterone vaginal gel.

FIG. 5 shows the in vitro dissolution data and profile of a progesteroneintravaginal ring of the present invention.

DETAILED DESCRIPTION OF THE INVENTION

The present invention relates to monolithic intravaginal ringscomprising progesterone, methods of making, and uses thereof. Theintravaginal rings comprise progesterone, a polysiloxane elastomer, anda pharmaceutically acceptable hydrocarbon or glycerol esters of a fattyacid.

Throughout the present disclosure, all expressions of percentage, ratio,and the like are “by weight” unless otherwise indicated. As used herein,“by weight” is synonymous with the term “by mass,” and indicates that aratio or percentage defined herein is done according to weight ratherthan volume, thickness, or some other measure.

As used herein, the term “about,” when used in conjunction with apercentage or other numerical amount, means plus or minus 10% of thatpercentage or other numerical amount. For example, the term “about 80%,”would encompass 80% plus or minus 8%.

The present invention is directed to a method for treating a lutealphase defect in a patient in need thereof, the method comprisingadministering to the patient a monolithic intravaginal ring comprising(a) a therapeutically effective amount of progesterone, (b) apolysiloxane elastomer, and (c) a pharmaceutically acceptablehydrocarbon or glycerol esters of a fatty acid.

The term “therapeutically effective amount” refers to an amount of thepharmaceutical composition (i.e., progesterone) that treats a condition,disorder, or disease in a subject. The precise therapeutic dosage ofprogesterone necessary to be therapeutically effective can vary betweensubjects (e.g., due to age, body weight, sex, condition of the subject,the nature and severity of the disorder or disease to be treated, andthe like). Thus, the therapeutically effective amount cannot always bespecified in advance, but can be determined by a caregiver, for example,by a physician using dose titration. Appropriate dosage amounts can alsobe determined by routine experimentation with animal models.

The terms “treat” and “treatment” refer to both therapeutic treatmentand prophylactic or preventative measures, wherein the object is toprevent or slow down (lessen) an undesired physiological condition,disorder or disease, or obtain beneficial or desired clinical results.For purposes of this invention, beneficial or desired clinical resultsinclude, but are not limited to, alleviation of symptoms; diminishmentof extent of condition, disorder or disease; stabilized (i.e., notworsening) state of condition, disorder or disease; delay in onset orslowing of condition, disorder or disease progression; amelioration ofthe condition, disorder or disease state, whether detectable orundetectable; or enhancement or improvement of condition, disorder ordisease. Treatment includes eliciting a clinically significant response,without excessive levels of side effects.

The term “luteal phase defect” refers to a disruption in the normalfemale menstrual cycle. The defect occurs when the female body does notproduce enough of the hormone progesterone. This results in a delay inthe development of the lining of the uterus (endometrium) during theluteal phase. The luteal phase is defined as the time between ovulationand the start of the next menstrual cycle. Luteal phase defects canresult in the inability to sustain a pregnancy, whereby the uterinelining begins to break down, bringing on menstrual bleeding and causingmiscarriage.

The present invention is directed to a method for treating a lutealphase defect in a patient in need thereof, the method comprisingadministering to the patient a monolithic intravaginal ring comprising(a) a therapeutically effective amount of progesterone, (b) apolysiloxane elastomer, and (c) a pharmaceutically acceptablehydrocarbon or glycerol esters of a fatty acid, wherein the polysiloxaneelastomer is present in a concentration of about 55% to about 90% bytotal weight of the ring.

The present invention is also directed to a method for treating a lutealphase defect in a patient in need thereof, the method comprisingadministering to the patient a monolithic intravaginal ring comprising(a) a therapeutically effective amount of progesterone, (b) apolysiloxane elastomer, and (c) a pharmaceutically acceptable oil,wherein the polysiloxane elastomer is present in a concentration ofabout 55% to about 90% by total weight of the ring.

The monolithic intravaginal ring of the present invention can be usefulas part of an assisted reproductive technology (ART) treatment forinfertile women with progesterone deficiency. The monolithicintravaginal ring of the present invention can be useful for lutealphase supplementation or replacement, e.g., partial luteal support forin vitro fertilization or complete luteal support for oocyte donation.The monolithic intravaginal ring of the present invention can also beuseful for the treatment of secondary amenorrhea.

The term “monolithic intravaginal ring” refers to a ring that is amatrix ring, wherein the matrix ring does not comprise a membrane orwall that encloses a reservoir.

The intravaginal ring provides for administration or application of anactive agent to the vaginal and/or urogenital tract of a subject,including, e.g., the vagina, cervix, or uterus of a female. In someembodiments, the intravaginal ring is annular in shape. As used herein,“annular” refers to a shape of, relating to, or forming a ring. Annularshapes suitable for use with the present invention include a ring, anoval, an ellipse, a toroid, and the like.

The intravaginal ring of the present invention can be flexible. As usedherein, “flexible” refers to the ability of a solid or semi-solid tobend or withstand stress and strain without being damaged or broken. Forexample, the intravaginal ring of the present invention can be deformedor flexed, such as, for example, using finger pressure (e.g., applyingpressure from opposite external sides of the device using the fingers),and upon removal of the pressure, return to its original shape. Theflexible properties of the intravaginal ring of the present inventionare useful for enhancing user comfort, and also for ease ofadministration to the vaginal tract and/or removal of the device fromthe vaginal tract.

The intravaginal ring of the present invention can be any size suitablefor placement in a vaginal tract. In some embodiments, the outsidediameter of the ring is about 35 mm to about 65 mm, about 40 mm to about60 mm, or about 45 mm to about 55 mm. In some embodiments, the outsidediameter of the ring is about 55 mm. As used herein, an “outsidediameter” refers to any straight line segment that passes through thecenter of the ring and whose endpoints are on the outer perimeter of thering, see, e.g., FIG. 1.

In some embodiments, the inside diameter of the ring is about 25 mm toabout 45 min, or about 30 mm to about 40 mm. In some embodiments, theinside diameter of the ring is about 38 mm. As used herein, an “insidediameter” refers to any straight line segment that passes through thecenter of the ring and whose endpoints are on the inner perimeter of thering, see, e.g., FIG. 1.

In some embodiments, the cross-sectional diameter of the ring is about 5mm to about 15 mm, or about 7 min to about 10 mm. In some embodiments,the cross-sectional diameter is about 8.5 mm. As used herein, a“cross-sectional diameter” refers to any straight line segment whoseendpoints are on the inner and outer perimeter of the ring, see, e.g.,FIG. 1.

In some embodiments, the monolithic intravaginal ring of the presentinvention comprises progesterone (pregn-4-ene-3,20-dione), asillustrated in Formula I.

In some embodiments, the progesterone can be micronized. As used herein,“micronized” refers to particles of a composition that have been reducedto micron size.

As used herein, the term “particle size” refers to particle diameter.Particle size and particle size distribution can be measured using, forexample, a Hyac/Royco particle size analyzer, a Malvern particle sizeanalyzer, a Beckman Coulter laser diffraction particle size analyzer, aShimadzu laser diffraction particle size analyzer, or any other particlesize measurement apparatus or technique known to persons of ordinaryskill in the art. As used herein, the term “particle diameter” relatesto a volumetric measurement based on an approximate spherical shape of aparticle. The present invention can also comprise semi-spherical,ellipsoidal, or cylindrical particles without limitation. In addition toencompassing progesterone particles of a given size, the presentinvention is also directed to compositions wherein the distribution ofparticle sizes of progesterone and excipients is controlled. As usedherein, a “distribution” refers to the number or concentration (i.e.,percentage) of particles having a certain size, or range of sizes,within a given lot, batch, or dosage form of the present invention.

Materials used in the intravaginal ring of the present invention aresuitable for placement in the vaginal tract, i.e., they are nontoxic andcan further be non-absorbable in the subject. In some embodiments, thematerials are compatible with an active agent. In some embodiments, thematerials can be capable of being suitably shaped for intravaginaladministration.

In some embodiments, the intravaginal ring comprises a polymer materialthat is an elastomer, e.g., a thermosetting elastomer, including, e.g.,a silicone co-polymer (thermosetting type). For example, theintravaginal ring of the present invention can be produced usingsilicone polymers which can include various catalysts or cross-linkingagents. Such silicone compounds, catalysts and cross-linking agents areknown in the art, see e.g., U.S. Pat. No. 4,888,074. A siliconecomposition can include any organo-silicone compound capable ofcross-linking, with or without the presence of cross-linking agents.

As used herein, an “elastomer” refers to an amorphous polymer networkformed when a polymer or a mixture of polymers undergo cross-linking.Each polymer is comprised of monomeric units, which are linked togetherto form the polymer. The monomeric units can comprise carbon, hydrogen,oxygen, silicon, halogen, or a combination thereof.

In some embodiments, the intravaginal ring comprises a polysiloxane. Asused herein, a “polysiloxane” refers to any of various compoundscontaining alternate silicon and oxygen atoms in either a linear orcyclic arrangement usually with one or two organic groups attached toeach silicon atom. For example, polysiloxanes include substitutedpolysiloxanes, and diorganopolysiloxanes such as diarylpolysiloxanes anddialkylpolysiloxanes; an example of the latter is dimethylpolysiloxane,as illustrated in Formula II.

Such dimethylpolysiloxane polymers can be thermoset to the correspondingelastomer by vulcanization with peroxide curing catalysts, e.g., benzoylperoxide or di-p-chlorobenzoyl peroxide at temperatures of about 200° C.and requiring additional heat after treatment as described in U.S. Pat.Nos. 2,541,137; 2,723,966; 2,863,846; 2,890,188; and 3,022,951.

An example of a two-component dimethylpolysiloxane composition, which isplatinum-catalyzed at room temperature or under slightly elevatedtemperature and capable of cross-linking, is MED-4840 (NuSil TechnologyLLC, Carpinteria, Calif.). In some embodiments of the present invention,a monolithic intravaginal ring can comprise progesterone, mineral oiland MED-4840 elastomer. The MED-4840 elastomer is composed of two parts,part A and part B. The chemical composition of MED-4840 part A comprisesdimethylpolysiloxane vinyl endblocked polymer, fumed silica(non-crystalline) trimethylsilyl treated and a platinum siliconecomplex. The chemical composition of MED-4840 part B comprises adimethylpolysiloxane vinyl endblocked polymer, fumed silica(non-crystalline) trimethylsilyl treated, dimethylmethylhydrogenpolysiloxane and 2-methyl-3-butyn-2-ol. Form A and form B undergocross-linkage to form a dimethylpolysiloxane elastomer.

In some embodiments of the present invention, the polysiloxane elastomeris a diorganopolysiloxane elastomer. In some embodiments, thediorganopolysiloxane elastomer is dimethylpolysiloxane elastomer. Insome embodiments, the dimethylpolysiloxane elastomer further comprises adimethylmethylhydrogen polysiloxane cross-link. In some embodiments ofthe present invention, the polysiloxane elastomer is MED-4840.

In some embodiments, the polysiloxane elastomer is present in aconcentration of about 55% to about 90% by total weight of the ring. Insome embodiments, the polysiloxane elastomer is present in aconcentration of about 60% to about 80% by total weight of the ring, orabout 65% to about 75% by total weight of the ring.

In some embodiments, the monolithic intravaginal ring comprises apharmaceutically-acceptable hydrocarbon or glycerol esters of a fattyacid. The glycerol esters of a fatty acid can be monoesters, diesters,triesters and mixtures thereof. The fatty acid glycerol esters can be ofa synthetic or natural origin. In some embodiments, the monolithicintravaginal ring comprises a pharmaceutically-acceptable oil. In someembodiments the oil can be a vegetable oil or a mineral oil. In someembodiments, the oil can be olive oil, peanut oil, lanoline, siliconeoil, mineral oil, glycerine fatty acids or combinations thereof.

In some embodiments, the pharmaceutically acceptable hydrocarbon orglycerol esters of a fatty acid is present in a concentration of about0.1% to about 10% by total weight of the ring. In some embodiments thepharmaceutically acceptable hydrocarbon or glycerol esters of a fattyacid is present in a concentration of about 1% to about 6% by totalweight of the ring. In some embodiments of the present invention, thepharmaceutically acceptable hydrocarbon or glycerol esters of a fattyacid is mineral oil.

In some embodiments, progesterone is substantially homogeneouslydispersed in the intravaginal ring. As used herein, “homogeneous” refersto a composition, e.g., the intravaginal ring, that has a substantiallyuniform distribution of ingredients throughout (i.e., an intravaginalring of the present invention does not have a composition gradient, or amulti-laminate structure).

In some embodiments, the progesterone is present in a concentration ofabout 1% to about 60% by total weight of the ring, in a concentration ofabout 10% to about 40% by total weight of the ring, in a concentrationof about 15% to about 30% by total weight of the ring, or in aconcentration of about 20% to about 25% by total weight of the ring.

In some embodiments, the intravaginal rings of the present inventionrelease about 10 mg to about 50 mg of progesterone/day in vitro, about10 mg to about 40 mg of progesterone/day in vitro, about 10 mg to about30 mg of progesterone/day in vitro, or about 10 mg to about 20 mg ofprogesterone/day in vitro.

In some embodiments, the intravaginal rings release about 14 mg to about28 mg of progesterone/day in vitro, about 16 mg to about 25 mg ofprogesterone/day in vitro, or about 18 mg to about 22 mg ofprogesterone/day in vitro. In some embodiments, the intravaginal ringreleases about 16 mg of progesterone/day in vitro. In some embodiments,the intravaginal ring releases about 19 mg of progesterone/day in vitro.

In some embodiments, the intravaginal rings release about 25 mg to about50 mg of progesterone/day in vitro, about 25 mg to about 40 mg ofprogesterone/day in vitro, about 30 mg to about 40 mg ofprogesterone/day in vitro, or about 32 mg to about 36 mg ofprogesterone/day in vitro.

As used herein, the “rate of release” or “release rate” refers to anamount or concentration of active agent that is released from theintravaginal ring over a defined period of time. The release rate can bemeasured in vitro by placing the ring into an Orbital shaker at 50 rpmcontaining 250 mL of 0.008 M SDS at 37° C. The active agent can beassayed by methods known in the art, e.g., by HPLC.

The intravaginal rings of the present invention can release about 10 mgto about 40 mg of progesterone/day in vivo, about 10 mg to about 30 mgof progesterone/day in vivo, about 10 mg to about 25 mg ofprogesterone/day in vivo, about 12 mg to about 25 mg of progesterone/dayin vivo, about 15 mg to about 25 mg of progesterone/day in vivo, about16 mg to about 24 mg of progesterone/day in vivo, about 17 mg to about22 mg of progesterone/day in vivo, or about 18 mg to about 22 mg ofprogesterone/day in vivo.

In some embodiments, the progesterone is released from the intravaginalring at a steady rate for up to about 18 days after administration to apatient, for up to about 14 days after administration to a patient, forup to about 7 days after administration to a patient, or for up to about4 days after administration to a patient.

In some embodiments, after the first day of administration to a patient,the progesterone is released at a steady rate for up to about 17additional days, for up to about 13 additional days, for up to about 6additional days, or for up to about 3 additional days afteradministration.

As used herein, a “steady rate” is a release rate that does not vary byan amount greater than about 70% of the amount of progesterone releasedin vivo per day, by an amount greater than about 60% of the amount ofprogesterone released in vivo per day, by an amount greater than about50% of the amount of progesterone released in vivo per day, by an amountgreater than about 40% of the amount of progesterone released in vivoper day, by an amount greater than about 30% of the amount ofprogesterone released in vivo per day, by an amount greater than about20% of the amount of progesterone released in vivo per day, by an amountgreater than about 10% of the amount of progesterone released in vivoper day, or by an amount greater than about 5% of the amount ofprogesterone released in vivo per day.

In some embodiments, the steady rate encompasses a release rate in vivoof about 15 mg/day to about 25 mg/day, about 16 mg/day to about 24mg/day, about 17 mg/day to about 22 mg/day or about 18 mg/day to about20 mg/day. In some embodiments, the steady rate encompasses a releaserate of about 12 mg/day to about 16 mg/day, about 12 mg/day to about 15mg/day, about 12 mg/day to about 14 mg/day, or about 12 mg/day to about13 mg/day. In some embodiments, the steady rate encompasses about 13mg/day to about 18 mg/day, about 13 mg/day to about 17 mg/day, about 13mg/day to about 16 mg/day, about 13 mg/day to about 15 mg/day, or about13 mg/day to about 14 mg/day. In some embodiments, the steady rateencompasses about 11 mg/day to about 15 mg/day, about 11 mg/day to about14 mg/day, about 11 mg/day to about 13 mg/day, or about 11 mg/day toabout 12 mg/day.

In some embodiments, the serum levels of progesterone are maintainedover a relatively constant level. In some embodiments, serumprogesterone levels are maintained at about 1 ng/mL to about 10 ng/mL,about 2 ng/mL to about 8 ng/mL, about 2 ng/mL to about 7 ng/mL, about 2ng/mL to about 6 ng/mL, about 3 ng/mL to about 6 ng/mL, about 4 ng/mL toabout 6 ng/mL, or about 5 ng/mL to about 6 ng/mL.

In some embodiments, serum progesterone levels are maintained at about 4ng/mL to about 10 ng/mL, about 4 ng/mL to about 9 ng/mL, about 5 ng/mLto about 8 ng/mL, or about 6 ng/mL to about 8 ng/mL.

In some embodiments, progesterone serum levels are maintained belowabout 7 ng/mL, below about 6 ng/mL, below about 5 ng/mL, below about 4ng/mL, below about 3 ng/mL, below about 2 ng/mL, or below about 1 ng/mL.

In some embodiments, these progesterone serum levels are maintained fromabout 1 day to about 18 days after administration to a patient, fromabout 1 day to about 14 days after administration to a patient, fromabout 1 day to about 10 days after administration to a patient, fromabout 1 day to about 7 days after administration to a patient, or fromabout 1 day to about 4 days after administration to a patient. In someembodiments, these progesterone serum levels are maintained from about 2days to about 18 days after administration to a patient, from about 2days to about 14 days after administration to a patient, from about 2days to about 7 days after administration to a patient, or from about 2days to about 4 days after administration to a patient.

In some embodiments, the present invention is directed to a monolithicintravaginal ring for treating a luteal phase defect in a patient inneed thereof, the ring comprising about 5% to about 40% by weight ofprogesterone, about 55% to about 90% by weight of polysiloxaneelastomer, and about 0.1% to about 10% by weight of a pharmaceuticallyacceptable hydrocarbon or glycerol esters of a fatty acid, wherein theprogesterone is homogeneously dispersed in the elastomer.

In some embodiments, the present invention is directed to a monolithicintravaginal ring for treating a luteal phase defect in a patient inneed thereof, the ring comprising about 5% to about 40% by weight ofprogesterone, about 55% to about 90% by weight of dimethylpolysiloxaneelastomer, and about 0.1% to about 10% by weight of mineral oil, whereinthe progesterone is homogeneously dispersed in the elastomer.

In some embodiments, the present invention is directed to a monolithicintravaginal ring for treating a luteal phase defect in a patient inneed thereof, the ring comprising about 10% to about 30% by weight ofprogesterone, about 60% to about 80% by weight of polysiloxaneelastomer, and about 1% to about 8% by weight of a pharmaceuticallyacceptable hydrocarbon or glycerol esters of a fatty acid, wherein theprogesterone is homogeneously dispersed in the elastomer.

In some embodiments, the present invention is directed to a monolithicintravaginal ring for treating a luteal phase defect in a patient inneed thereof, the ring comprising about 10% to about 30% by weight ofprogesterone, about 60% to about 80% by weight of dimethylpolysiloxaneelastomer, and about 1% to about 8% by weight of a mineral oil, whereinthe progesterone is homogeneously dispersed in the elastomer.

In some embodiments, the present invention is directed to a monolithicintravaginal ring for treating a luteal phase defect in a patient inneed thereof, the ring comprising about 20% to about 25% by weight ofprogesterone, about 65% to about 75% by weight of polysiloxaneelastomer, and about 1% to about 6% by weight of a pharmaceuticallyacceptable hydrocarbon or glycerol esters of a fatty acid, wherein theprogesterone is homogeneously dispersed in the elastomer.

In some embodiments, the present invention is directed to a monolithicintravaginal ring for treating a luteal phase defect in a patient inneed thereof, the ring comprising about 20% to about 25% by weight ofprogesterone, about 65% to about 75% by weight of dimethylpolysiloxaneelastomer, and about 1% to about 6% by weight of a mineral oil, whereinthe progesterone is homogeneously dispersed in the elastomer, andwherein the progesterone is released from the monolithic intravaginalring for about 18 days after administration to the patient.

The invention is directed to a process for making a monolithicintravaginal ring, the process comprising (a) mixing progesterone, apharmaceutically acceptable hydrocarbon or glycerol esters of a fattyacid, and a polysiloxane to form a homogeneous mixture, (b) placing thehomogeneous mixture into a mold and, (c) curing the homogeneous mixturein the mold to form a monolithic intravaginal ring comprising apolysiloxane elastomer, the progesterone, and the pharmaceuticallyacceptable hydrocarbon or glycerol esters of a fatty acid. In someembodiments of the present invention, the polysiloxane is vinyl endblocked.

In some embodiments, the mold is cured at about 60° C. to about 180° C.,about 70° C. to about 150° C., about 80° C. to about 120° C., or about85° C. to about 95° C. In some embodiments, the ring is cured outsidethe mold. In some embodiments, the process further comprises mixing asecond polysiloxane into the homogeneous mixture prior to placing itinto the mold. In some embodiments, the second polysiloxane is across-linker. In some embodiments, the cross-linker isdimethylmethylhydrogen polysiloxane. In some embodiments, the placing ofthe homogeneous mixture into the mold is by injection.

The present invention is directed to a method for treating a lutealphase defect in a patient in need thereof, the method comprisingadministering to a patient a monolithic intravaginal ring comprising (a)progesterone, (b) a dimethylpolysiloxane elastomer, and (c) apharmaceutically acceptable hydrocarbon or glycerol esters of a fattyacid, wherein the ratio of progesterone to elastomer is about 1:1 toabout 1:10, the progesterone is homogeneously dispersed in theelastomer, the ratio of progesterone to hydrocarbon or glycerol estersof a fatty acid is about 1:0.1 to about 1:100, and wherein theprogesterone is released from the monolithic intravaginal ring for up toabout 18 days after administration to the patient.

In some embodiments, the ratio of progesterone to elastomer is about 1:1to about 1:10, about 1:1 to about 1:8, about 1:1 to about 1:6, about 1:1to about 1:4, or about 1:2 to about 1:5.

In some embodiments, the ratio of progesterone to hydrocarbon orglycerol esters of a fatty acid is about 1:0.1 to about 1:100, about1:0.1 to about 1:50, about 1:0.1 to about 1:25, about 1:0.1 to about1:10, or about 1:0.1 to about 1:1.

The present invention is directed to a method for treating a lutealphase defect in a patient in need thereof, the method comprisingadministering to a patient a monolithic intravaginal ring comprising (a)progesterone, (b) a dimethylpolysiloxane elastomer, and (c) apharmaceutically acceptable hydrocarbon or glycerol esters of a fattyacid, in a ratio of about 4:15:1, respectively (by weight), wherein theprogesterone is homogeneously dispersed in the elastomer, and whereinthe progesterone is released from the monolithic intravaginal ring forup to about 18 days after administration to the patient.

The present invention is directed to a method for treating a lutealphase defect in a patient in need thereof, the method comprisingadministering to a patient a monolithic intravaginal ring comprising (a)progesterone, (b) a dimethylpolysiloxane elastomer, and (c) apharmaceutically acceptable hydrocarbon or glycerol esters of a fattyacid, in a ratio of about 20:90:1, respectively (by weight), wherein theprogesterone is homogeneously dispersed in the elastomer, and whereinthe progesterone is released from the monolithic intravaginal ring forup to about 18 days after administration to the patient.

The present invention is directed to a method for treating a lutealphase defect in a patient in need thereof, the method comprisingadministering to a patient a monolithic intravaginal ring comprising (a)progesterone, (b) a dimethylpolysiloxane elastomer, and (c) apharmaceutically acceptable hydrocarbon or glycerol esters of a fattyacid, in a ratio of about 40:40:1, respectively (by weight), wherein theprogesterone is homogeneously dispersed in the elastomer, and whereinthe progesterone is released from the monolithic intravaginal ring forup to about 18 days after administration to the patient.

The present invention is directed to a method for treating a lutealphase defect in a patient in need thereof, the method comprisingadministering to the patient a monolithic intravaginal ring comprising(a) about 10% to about 40% by weight of progesterone, (b) about 55% toabout 90% by weight of a dimethylpolysiloxane elastomer, and (c) about0.1% to about 10% by weight of a pharmaceutically acceptable hydrocarbonor glycerol esters of a fatty acid, wherein the progesterone ishomogeneously dispersed in the elastomer, and wherein the progesteroneis released from the monolithic intravaginal ring for up to about 18days after administration to the patient.

The present invention is directed to a method for treating a lutealphase defect in a patient in need thereof, the method comprisingadministering to the patient a monolithic intravaginal ring comprising(a) about 15% to about 25% by weight of progesterone, (b) about 70% toabout 80% by weight of a dimethylpolysiloxane elastomer, and (c) about1% to about 10% by weight of a pharmaceutically acceptable hydrocarbonor glycerol esters of a fatty acid, wherein the progesterone ishomogeneously dispersed in the elastomer, and wherein the progesteroneis released from the monolithic intravaginal ring for up to about 18days after administration to the patient.

In some embodiments, the intravaginal ring is replaced with a new ringafter about 18 days following administration to the patient, after about14 days following administration to the patient, after about 10 daysfollowing administration to the patient, after about 7 days followingadministration to the patient, after about 5 days followingadministration to the patient, after about 4 days followingadministration to the patient, after about 3 days followingadministration to the patient, or after about 2 days followingadministration to the patient. In accordance with the present invention,the intravaginal ring is not maintained longer than about 20 days beforeit is replaced with a new ring.

The intravaginal ring can be administered about one to seven days beforeembryo transfer, about two to six days before embryo transfer, about twoto five days before embryo transfer, or about three to four days beforeembryo transfer. The administration of the intravaginal ring can besupplemented by other hormone administration, for example oraladministration of estradiol.

In some embodiments, progesterone is administered via the intravaginalring of the present invention for about 10 weeks, for about 8 weeks, forabout 6 weeks, for about 4 weeks, for about 2 weeks, or for about 1week.

In some embodiments, the present invention is directed to a method fortreating a luteal phase defect in a patient in need thereof, the methodcomprising administering to the patient a monolithic intravaginal ringcomprising (a) progesterone, (b) MED-4840, and (c) a pharmaceuticallyacceptable hydrocarbon or glycerol esters of a fatty acid, wherein theratio of progesterone to MED-4840 is about 1:1 to about 1:10, theprogesterone is homogeneously dispersed in the elastomer, the ratio ofprogesterone to hydrocarbon or glycerol esters of a fatty acid is about1:0.1 to about 1:100, wherein the progesterone is released from theintravaginal ring at about 15 mg/day to about 25 mg/day in vivo, andwherein the intravaginal ring is replaced after about every 7 daysfollowing administration to the patient.

In some embodiments, the present invention is directed to a method fortreating a luteal phase defect in a patient in need thereof, the methodcomprising administering to the patient a monolithic intravaginal ringcomprising (a) progesterone, (b) a dimethylpolysiloxane elastomer, and(c) mineral oil, in a ratio of about 4:15:1, respectively, wherein theprogesterone is homogeneously dispersed in the elastomer, and releasedfrom the intravaginal ring at about 15 mg/day to about 25 mg/day invivo, and wherein the intravaginal ring is replaced after about every 7days following administration to the patient.

In some embodiments, the present invention is directed to a method fortreating a luteal phase defect in a patient in need thereof, the methodcomprising administering to a patient a monolithic intravaginal ringcomprising (a) about 20% progesterone, (b) about 75% MED-4840, and (c)about 5% mineral oil, wherein the progesterone is homogeneouslydispersed in the elastomer, wherein the progesterone is released fromthe intravaginal ring at about 15 mg/day to about 25 mg/day in vivo, andwherein the intravaginal ring is replaced after about every 7 daysfollowing administration to the patient.

The following examples are for the purpose of illustration of theinvention only and are not intended in any way to limit the scope of thepresent invention. It will thus be readily apparent to one skilled inthe art that varying substitutions and modifications may be made to theinvention disclosed herein without departing from the scope and spiritof the invention.

EXAMPLES Example 1

FIG. 2 depicts a process flow chart representing a process for preparinga monolithic intravaginal ring of the present invention. Micronizedprogesterone, MED-4840 elastomer part A, and mineral oil were combinedto form a homogeneous mixture (“the part A mix”). Micronizedprogesterone, MED-4840 elastomer part B, and mineral oil were combinedto form a second homogeneous mixture (“the part B mix”).

The part A mix was prepared by placing about 20% (by weight of the finalproduct) micronized progesterone, about 75% (by weight of the finalproduct) MED-4840 part A polysiloxane, and about 5% (by weight of thefinal product) mineral oil in a Ross DPM-4 mixer (Ross double planetarymixer and dispenser supplied by Charles Ross & Son, Hauppauge, N.Y.),where the ingredients were mixed and degassed under vacuum for about 30minutes. The part A mix was then transferred to pre-weighed disposablecartridges.

The part B mix was prepared by placing about 20% (by weight of the finalproduct) micronized progesterone, about 75% (by weight of the finalproduct) MED-4840 part B polysiloxane and about 5% (by weight of thefinal product) mineral oil in a Ross DPM-4 mixer, where the ingredientswere mixed and degassed under vacuum for about 30 minutes. The part Bmix was then transferred to pre-weighed disposable cartridges.

The part A mix and the part B mix cartridges were then placed onseparate pumps of a Gluco P20LS injection molding machine (supplied byGluco, Jenison, Mich.). The machine then injected both the A and B mixesat a 1:1 ratio into a static mixer to produce a homogeneous mix in-line.The in-line homogeneous mix was immediately injected into a multi-cavitymold for filling at ambient temperature.

The filled molds were removed from the machine and transferred to aGrieve oven (Grieve Corp., Round Lake, Ill.) for curing at about 90° C.for about eight hours. The molds were then allowed to cool to roomtemperature and disassembled to remove the rings. Entry and exit runnersand flashing were removed from the rings, which were then trimmed priorto packaging in heat-sealed foil pouches.

The process yielded a monolithic intravaginal ring with a composition aslisted in Table 1, with an outside diameter of about 55 mm, an insidediameter of about 38 mm, and a cross-sectional diameter of about 8.5 mm(as depicted in FIG. 1).

The in vitro dissolution profile of the intravaginal ring was determinedusing an Orbital shaker containing 250 mL of 0.008 M SDS at 37° C. at 50rpm. These results are listed in FIG. 5. When administered to thevaginal tract of a patient, the intravaginal ring releases about 10mg/day to about 30 mg/day of progesterone over about 7 days.

TABLE 1 Composition of the monolithic intravaginal ring of Example 1(mass/g) (% wt of ring) Micronized Progesterone 1.8 20 Mineral Oil 0.455 MED-4840 Part A 3.375 37.5 MED-4840 Part B 3.375 37.5 Total 9.000 100

Example 2

A pharmacodynamic study to compare an intravaginal ring of Example 1 toa progesterone vaginal gel for luteal phase replacement was conducted.

This was a single-center, open-label, randomized, active-controlled,comparative, pharmacodynamic study to evaluate a single dose ofprogesterone, delivered by vaginal ring, for resultant endometrialtransformation and luteal phase replacement. The study had 2 treatmentarms. One investigator enrolled and randomized 20 eligible women aged18-50, with 10 women per treatment arm (21 subjects were randomized andone subject discontinued from the vaginal gel treatment arm when she wasfound to have cervical dysplasia on her Pap smear). The overall studyduration for each patient was approximately 1½ months. The subjectdemographics are shown in Table 2.

TABLE 2 Subject Demographics Mock Cycle ET Cycle ProgesteroneProgesterone Progesterone Progesterone Vaginal Ring Vaginal Gel VaginalRing Vaginal Gel N = 10 N = 11 N = 5 N = 4 Race: African- 2 (20.0%) 3(27.3%) 1 (20.0%) 0 (0.0%) American Caucasian 8 (80.0%) 8 (72.7%) 4(80.0%) 4 (100%) Age (yrs): Mean (SD) 41.0 (5.42) 39.1 (6.12) 43.0(3.39) 39.8 (7.23) Min/Max 30.0/47.0 30.0/49.0 38.0/47.0 33.0/50.0 BodyMass Index (kg/m²): Mean (SD) 27.7 (4.84) 27.5 (6.73) 25.4 (2.0) 25.2(3.63) Min/Max 21.7/36.9 19.6/40.5 23.2/27.5 20.2/28.4

All patients met all inclusion and none of the exclusion criteria asspecified in the protocol. Continued participation in the study dependedon the patient meeting the protocol requirement at the randomizationvisit. The study duration was 31 days plus two weeks of post-treatmentfollow-up. In the first 14 days, estradiol pre-treatment was given inattempt to generate a proliferative phase of the endometrium.

Subjects enrolled in the mock cycle received oral contraceptive pills(“OCPs”) for 2 weeks and a GnRH agonist (Lupron®, TAP Pharmaceuticals,Chicago, Ill.) to suppress ovarian function. The GnRH agonist wasinitiated on day 8 of the OCPs in the cycle preceding the mock and/ortransfer cycle and continued until estradiol patches were initiated. Theestradiol regimen was determined by the site's mock cycle protocoland/or the clinical investigator's discretion. Estradiol pre-treatmentwas generally administered in a step-up fashion (0.2 mg days 1-7, 0.3 mgdays 8-11 and 0.4 mg days 12-14 every other day, Vivelle patches) togenerate a proliferative phase of the endometrium.

Subjects with an endometrial thickness >6 mm were randomized in a 1:1fashion to either a progesterone intravaginal ring (10-30 mg/day,Duramed Research, Inc., Bala Cynwyd, PA) or a progesterone vaginal gel(Crinone®, 180 mg/day, Columbia Laboratories, Inc., Livingston, N.J.)and taught to administer the product. A progesterone intravaginal ring10-30 mg/day (in vitro release rate) or progesterone vaginal gel (180mg/day), together with estradiol (per the site's protocol, e.g., 0.2mg/day), was administered over the next 18 days to transform theendometrium to the secretory phase. The progesterone intravaginal ringwas replaced one time on day 8, while the vaginal gel was administeredtwice a day for the full 18 days of progesterone dosing. Serumprogesterone and estradiol samples were collected at cycle day 0, 14,15, 16, 18, 21, 22, 23, 25, 28, and 31. An endometrial biopsy wasperformed on cycle day 25 or 26 and endometrial dating was performedaccording to Noyes et al., Fertil. Steril., 1:3-25 (1950). Intravaginalring compliance was determined at each study visit. Vaginal colposcopywas performed at screening and on cycle day 31 to determine whetherthere was potential vaginal and cervical irritation.

The objectives of the study were to determine in women with clinical ormedically-induced agonadism (who were administered the intravaginalring) (a) the proportion of patients with adequate endometrialtransformation (on endometrial biopsy) as determined by histologicaldating of the endometrium, (b) progesterone and estradiol levels in theserum obtained from patients, and (c) the safety and tolerability ofprogesterone delivered by an intravaginal ring as compared with aprogesterone vaginal gel. The study was performed on twenty patientswith an estrogen-primed endometrium.

Subjects were women aged 18-50 with clinical or medically-inducedagonadism who were eligible for oocyte donation. Subjects with a historyof more than two failed donor egg cycles, significant prior uterinesurgery, hysterectomy, or clinically significant uterine pathology wereexcluded from the study.

The intravaginal ring of Example 1 was administered to the subject, andthe duration of the dosing regimen lasted 18 days, wherein theintravaginal ring was replaced once in the 18 day period, on day 8. Insubjects that were administered the progesterone vaginal gel, thevaginal application of 180 mg/day for 18 days was dosed at 90 mg twice aday.

The primary efficacy measure was the presence or absence of adequatesecretory transformation of the endometrium as determined by biopsy oneither cycle day 25 or 26. The proportion of patients having an in-phasebiopsy and adequate endometrial secretory transformation determined byhistological dating of the endometrium, as defined by the histologicaltest results, was calculated. The intravaginal ring of Example 1adequately transformed the endometrium to secretory phase in 8 out of 10patients while the vaginal gel 180 mg/day did so in 10 out of 10patients.

However, additional outside factors may have contributed to the failurein the two patients who did not exhibit endometrial transformation. Onesubject had a non-datable endometrium; predominantly inactive with tubalmetaplasia, but showing small foci of secretory exhaustion, suggestiveof an uneven end-organ response to the hormonal milieu (i.e., irregularripening). There was a fibroid found in surgery post-study, which couldhave affected blood supply to the endometrium. Post-surgery, the subjectwent through a mock cycle with micronized progesterone 200 mg t.i.d. andunderwent a biopsy that showed adequate transformation. This samesubject underwent a donor egg 1VF using micronized progesterone thatresulted in a negative βhCG. The subject is considering one more IVFattempt with a donor egg. The second subject was a 37 year-old withgonadal dysgenesis (streak ovaries and ovarian failure) and no periodssince birth who exhibited a mixed inactive and exhausted secretoryendometrium; features favored late secretory phase, but no precisedating was possible. This subject was screened twice for the study, andafter the first estradiol pre-treatment had an endometrial lining <6 mm.The subject was allowed to re-screen for the study; and after the secondscreening and estradiol pre-treatment, the subject had an endometriallining >6 mm. Post-study, the subject went through a mock cycle with IMprogesterone, and underwent a biopsy that showed adequatetransformation. This same subject underwent a donor egg IVF using IMprogesterone (50 mg) that resulted in a positive βhCG and an ongoingpregnancy with delivery.

Estradiol serum levels in the intravaginal ring treatment group werecomparable with that of the Crinone® group, while progesterone serumlevels in the intravaginal ring treatment group were on average lowerthan those for Crinone® (6.02 ng/mL vs. 14.18 ng/mL). Estradiol serumlevels of the treatment groups at various time points is shown below inTable 3 and schematically in FIG. 3. Progesterone serum levels of thetreatment groups at various time points is shown below in Table 4 andschematically in FIG. 4.

TABLE 3 Estradiol Serum Levels and Changes During the Study EstradiolProgesterone Vaginal Ring 8% Progesterone Vaginal Gel (ng/mL) NMean(Std) Median (Min, Max) N Mean(Std) Beginning 10 19.8 (16.29) 10.0(10.0, 61.0)  10 32.4 (44.61) Cycle Day 14 10 280.4 (91.69) 264.0(172.0, 410.0)  10 345.1 (100.85) Change from 10 260.6 (86.82) 242.5(162.0, 394.0)  10 312.7 (121.15) Beginning to Day 14 10 229.0 (145.69)205.0 (108.0, 616.0)  10 283.0 (111.48) Cycle Day 15 Change from 10209.2 (148.51) 180.0 (98.0, 606.0) 10 250.6 (118.12) Beginning to Day 1510 188.2 (93.35) 160.5 (61.6, 346.0) 10 229.9 (102.28) Cycle Day 16Change from 10 168.4 (87.00) 150.5 (50.0, 293.0) 10 197.5 (112.30)Beginning to Day 16 10 198.2 (74.44) 199.5 (84.1, 322.0) 10 232.9(145.87) Cycle Day 18 Change from 10 178.4 (71.55) 172.0 (61.1, 296.0)10 200.5 (159.59) Beginning to Day 18 10 216.5 (139.59) 167.5 (64.8,496.0) 10 186.6 (82.09) Cycle Day 21 Change from 10 196.7 (142.31) 143.0(41.8, 486.0) 10 154.2 (96.53) Beginning to Day 21 10 221.0 (126.25)184.0 (76.5, 504.0) 10 259.1 (86.13) Cycle Day 22 Change from 10 201.2(119.09) 174.0 (53.5, 478.0) 10 226.7 (95.57) Beginning to Day 22 10236.8 (146.75) 157.5 (92.0, 514.0) 10 212.7 (79.13) Cycle Day 23 Changefrom 10 217.0 (144.87) 141.0 (64.0, 504.0) 10 180.3 (75.48) Beginning toDay 23 10 190.5 (81.33) 169.0 (100.0, 355.0)  10 193.1 (145.48) CycleDay 25 Change from 10 170.7 (77.35) 156.5 (90.0, 329.0) 10 160.7(123.48) Beginning to Day 25 10 223.7 (104.99) 184.0 (102.0, 418.0)  10282.1 (158.28) Cycle Day 28 Change from 10 203.9 (98.75) 174.0 (79.0,392.0) 10 249.7 (153.35) Beginning to Day 28 10 124.2 (73.10) 123.0(34.0, 296.0) 10 115.3 (63.02) Cycle Day 31 Change from 10 104.4 (69.67)96.0 (24.0, 270.0) 10 82.9 (54.81) Beginning to Day 31 Estradiol 8%Progesterone Vaginal Gel Total (ng/mL) Median (Min, Max) N Mean(Std)Median (Min, Max) Beginning 10.0 (10.0, 152.0) 20 26.1 (33.32) 10.0(10.0, 152.0) Cycle Day 14 339.0 (232.0, 498.0)  20 312.8 (99.50) 304.0(172.0, 498.0)  Change from 318.5 (110.0, 488.0)  20 286.7 (106.01)277.5 (110.0, 488.0)  Beginning to Day 14 274.5 (141.0, 453.0)  20 256.0(129.26) 208.5 (108.0, 616.0)  Cycle Day 15 Change from 201.5 (112.0,443.0)  20 229.9 (132.31) 181.5 (98.0, 606.0) Beginning to Day 15 207.5(65.9, 408.0) 20 209.0 (97.68) 192.0 (61.6, 408.0) Cycle Day 16 Changefrom 188.0 (25.0, 398.0) 20 182.9 (98.91) 169.0 (25.0, 398.0) Beginningto Day 16 186.5 (102.0, 501.0)  20 215.6 (114.11) 198.0 (84.1, 501.0)Cycle Day 18 Change from 176.5 (−50.0, 491.0)  20 189.5 (120.90) 172.0(−50.0, 491.0)  Beginning to Day 18 172.5 (66.0, 351.0) 20 201.5(112.50) 167.5 (64.8, 496.0) Cycle Day 21 Change from 152.5 (13.0,341.0) 20 175.4 (120.34) 152.5 (13.0, 486.0) Beginning to Day 21 226.0(187.0, 436.0)  20 240.0 (106.99) 201.5 (76.5, 504.0) Cycle Day 22Change from 201.0 (74.0, 380.0) 20 213.9 (105.90) 183.0 (53.5, 478.0)Beginning to Day 22 191.5 (135.0, 382.0)  20 224.8 (115.41) 172.5 (92.0,514.0) Cycle Day 23 Change from 156.5 (106.0, 372.0)  20 198.7 (113.99)151.5 (64.0, 504.0) Beginning to Day 23 142.5 (63.8, 539.0) 20 191.8(114.72) 154.5 (63.8, 539.0) Cycle Day 25 Change from 123.0 (53.8,483.0) 20 165.7 (100.41) 135.0 (53.8, 483.0) Beginning to Day 25 309.0(88.9, 610.0) 20 252.9 (134.11) 212.0 (88.9, 610.0) Cycle Day 28 Changefrom 247.0 (78.9, 600.0) 20 226.8 (127.72) 192.5 (78.9, 600.0) Beginningto Day 28 96.0 (47.0, 234.0) 20 119.7 (66.58) 112.5 (34.0, 296.0) CycleDay 31 Change from 71.5 (17.0, 178.0) 20 93.6 (62.00) 79.5 (17.0, 270.0)Beginning to Day 31

TABLE 4 Progesterone Serum Levels and Changes During the StudyProgesterone Progesterone Vaginal Ring 8% Progesterone Vaginal Gel Total(ng/mL) N Mean(Std) Median (Min, Max) N Mean(Std) Median (Min, Max) NMean(Std) Median (Min, Max) Beginning 10 0.9 (0.71) 0.6 (0.2, 2.5) 100.9 (0.32) 0.9 (0.6, 1.6)  20 0.9 (0.53) 0.8 (0.2, 2.5)  Cycle Day 14 100.7 (0.33) 0.7 (0.1, 1.4) 10 0.8 (0.24) 0.8 (0.5, 1.2)  20 0.7 (0.28)0.7 (0.1, 1.4)  Change from 10 −0.2 (0.54)  −0.1 (−1.5, 0.5)  10 −0.1(0.21) −0.2 (−0.6, 0.2)  20 −0.2 (0.40) −0.1 (−1.5, 0.5)  Beginning toDay 14 10 5.2 (2.00) 4.7 (3.3, 9.0) 10 11.9 (6.48) 11.6 (3.6, 26.0) 208.5 (5.79) 6.6 (3.3, 26.0) Cycle Day 15 Change from 10 4.3 (1.77) 3.4(2.7, 7.3) 10 10.9 (6.46) 10.5 (2.6, 25.2) 20 7.6 (5.75) 5.8 (2.6, 25.2)Beginning to Day 15 10 5.6 (1.85) 5.6 (3.5, 9.2) 10 13.3 (3.95) 14.0(5.8, 19.7) 20 9.4 (4.96) 8.5 (3.5, 19.7) Cycle Day 16 Change from 104.7 (1.73) 4.5 (3.0, 8.5) 10 12.4 (3.89) 12.6 (5.2, 18.9) 20 8.5 (4.92)7.3 (3.0, 18.9) Beginning to Day 16 10 6.7 (1.96) 7.1 (4.0, 9.5) 10 13.0(4.76) 12.8 (6.9, 23.4) 20 9.8 (4.80) 8.7 (4.0, 23.4) Cycle Day 18Change from 10 5.8 (1.90) 5.7 (3.4, 8.9) 10 12.0 (4.79) 11.9 (6.3, 22.6)20 8.9 (4.80) 7.7 (3.4, 22.6) Beginning to Day 18 10 6.6 (1.70) 5.9(4.6, 9.4) 10 13.2 (4.81) 12.2 (7.4, 22.4) 20 9.9 (4.89) 8.7 (4.6, 22.4)Cycle Day 21 Change from 10 5.7 (1.80) 5.2 (3.2, 8.8) 10 12.3 (4.77)11.3 (6.8, 21.6) 20 9.0 (4.89) 7.7 (3.2, 21.6) Beginning to Day 21 106.5 (2.00) 6.2 (3.9, 9.7) 10 14.8 (6.02) 15.8 (6.6, 26.3) 20 10.6 (6.11)8.7 (3.9, 26.3) Cycle Day 22 Change from 10 5.5 (2.01) 5.0 (3.4, 8.5) 1013.9 (6.00) 14.5 (6.0, 25.5) 20 9.7 (6.10) 7.9 (3.4, 25.5) Beginning toDay 22 10 6.5 (1.80) 6.5 (3.5, 9.3) 10 16.9 (10.31) 14.5 (7.2, 38.5) 2011.7 (8.98) 7.9 (3.5, 38.5) Cycle Day 23 Change from 10 5.6 (1.92) 5.3(3.0, 8.7) 10 16.0 (10.33) 13.5 (5.9, 37.7) 20 10.8 (9.00) 7.2 (3.0,37.7) Beginning to Day 23 10 5.7 (1.54) 5.8 (3.7, 7.8) 10 14.7 (6.37)16.2 (5.4, 26.8) 20 10.2 (6.46) 7.1 (3.7, 26.8) Cycle Day 25 Change from10 4.8 (1.48) 4.7 (3.1, 7.4) 10 13.8 (6.42) 15.2 (4.8, 26.0) 20 9.3(6.47) 6.1 (3.1, 26.0) Beginning to Day 25 Cycle Day 28 10 5.7 (1.38)6.0 (3.8, 8.0) 10 15.1 (7.19) 15.7 (6.2, 29.0) 20 10.4 ( 6.96) 6.9 (3.8,29.0) Change from 10 4.8 (1.46) 4.7 (3.2, 7.8) 10 14.2 (7.07) 15.0 (5.5,27.7) 20 9.5 (6.91) 5.9 (3.2, 27.7) Beginning to Day 28 Cycle Day 31 105.7 (1.52) 5.5 (3.2, 8.1) 10 14.7 (6.54) 14.4 (3.7, 27.3) 20 10.2 (6.51)7.7 (3.2, 27.3) Change from 10 4.8 (1.52) 4.7 (2.6, 7.7) 10 13.7 (6.57)13.8 (3.1, 26.5) 20 9.3 (6.52) 6.6 (2.6, 26.5) Beginning to Day 31

Also in this study the intravaginal ring was observed to be as safe asthe vaginal gel, except for the observation that most patients in theintravaginal ring treatment group had mild vaginal bleeding/spottingnear the end of the treatment. A summary of breakthroughbleeding/spotting for the treatment groups and in individual subjects isshown in Tables 5 and 6, respectively.

TABLE 5 Vaginal Bleeding/Spotting During Study for the Treatment Groups8% Progesterone Progesterone Vaginal Ring Vaginal Gel Total Visit (N =10) (N = 11) (N = 21) Total Bleeding/ 9 (90.00)  5 (45.45) 14 (66.67) Spotting Patients Cycle Day 25 5 (50.00)  4 (36.36) 9 (42.86) Cycle Day26 4 (40.00)  3 (27.27) 7 (33.33) Cycle Day 27 4 (40.00) 1 (9.09) 5(23.81) Cycle Day 28 6 (60.00) 0 (0.00) 6 (28.57) Cycle Day 29 8 (80.00)0 (0.00) 8 (38.10) Cycle Day 30 9 (90.00) 0 (0.00) 9 (42.86) Cycle Day31 7 (70.00) 0 (0.00) 7 (33.33)

TABLE 6 Summary of Breakthrough Vaginal Bleeding/Spotting in IndividualSubjects Vaginal Endometrial Biopsy Results Vaginal bleeding Vaginalbleeding Cycle Day by after biopsy, but bleeding Patient Study beforeHistologic before Visit 9 on/after Visit 9 # Drug biopsy? Phase Dating(Cycle Day 28)? (Cycle Day 28)? AEs reported 0103 VR Secretory 23Metrorrhagia, Onychomycosis 0105 VR Inactive N/A Metrorrhagia, Myalgia0107 VR Secretory 23 light spotting light spotting Metrorrhagia, LimbDiscomfort 0109 VR Secretory 24 light spotting light spottingMetrorrhagia, Dysmenorrhoea 0113 VR Secretory 23 Metrorrhagia 0114 VRSecretory 25 light spotting Metrorrhagia, Nasopharyngitis 0123 VR CycleDay Mixed Pattern N/A Vaginal Discharge, 21, Upper Respiratory ScantTract Infection amount of (URTI), Skin pink Irritation tinged mucous onVR 0124 VR Secretory  25** light spotting Metrorrhagia 0127 VR Secretory23 red/brown spotting Metrorrhagia, Nausea 0129 VR Secretory 25 SpottingMetrorrhagia, URTI, Ear Pain, Breast Discomfort, Post ProceduralComplication 0102 Gel Secretory 25 moderate to heavy N/A 0106 GelSecretory 23 light spotting Pelvic Pain, Sinus Headaches,Pharyngolaryngeal Pain 0108 Gel Secretory 23 Nausea 0111 Gel Prior toSecretory 24 light spotting Headaches, URTI Visit 1, moderate to heavy0115 Gel Secretory 25 URTI, Uterine Cervical Erosion, Vaginal Erosion0122 Gel Prior to Secretory 24 light spotting Metrorrhagia, Visit 0 -Headache, during Withdrawal Bleed, estradiol Dysmenorrhoea pre-treatment (moderate) 0125 Gel Secretory 25 Vulvovaginal DiscomfortAbdominal Pain, Post Procedural Complication 0126 Gel Secretory 25 onespec dry blood Breast Discomfort, Cervical Polyp, Abdominal Pain 0128Gel Secretory 24 light spotting Abdominal Pain, Post ProceduralComplication 0130 Gel Secretory 24 Abdominal Pain Lower *vaginalbleeding after biopsy cases were reported by the site via email orphone; vaginal bleeding after biopsy was not considered an AE, as it isan expected result of the procedure; therefore, the above informationwas not captured on the CRFs, nor entered into the database **patchydecidualization of stroma giving a range of appearances from POD 8 toPOD 11

Subjects with adequate secretory endometrial transformation in the mockcycle who had accepted an oocyte donor and were synchronized with thisdonor were invited to participate in a follow-on embryo transfer cycle.Subjects were kept on the same progesterone treatment to which they hadbeen randomized in the mock cycle. For subjects in the intravaginal ringgroup, a new intravaginal ring was placed at the time of transfer, andthe intravaginal ring was scheduled to be replaced weekly until thepregnancy test was performed 2 weeks after embryo transfer. Subjects inthe vaginal gel group continued to self-administer the vaginal gel twicedaily until 2 weeks after embryo transfer. If a pregnancy was detected,the estradiol replacement was continued for a total of 8 weeks and theprogesterone for a total of 10 weeks after embryo transfer. Pelvicultrasound was performed at 8 weeks and 12 weeks to confirm a clinicalpregnancy. Follow-up of any pregnancies continued until delivery.

Biochemical pregnancy, clinical pregnancy (8 and 12 weeks of pregnancy),and live birth rates were assessed. A biochemical pregnancy was definedas a transient increase in hCG levels, followed by a decrease. Aclinical pregnancy was defined by the visualization of a gestational sacwith fetal heart motion on ultrasound. The primary efficacy measure inthe embryo transfer cycle was the clinical pregnancy rate at 8 weeks ofpregnancy, where the gestational age (duration of pregnancy) in weekswas defined as commencing 2 weeks prior to embryo transfer, which wouldcorrelate in a normally ovulating and cycling woman with the first dayof her last menstrual period. Secondary outcome measures in the embryotransfer cycle included clinical pregnancy rates at 12 weeks ofpregnancy and live birth rates.

A total of 11 subjects consented, with 9 subjects undergoing an embryotransfer. There were a total of 5 transfers in the intravaginal ringtreatment group and 4 in the vaginal gel treatment group. Of thesetransfers, 4 of 5 (80%) intravaginal ring subjects and 1 of 4 (25%)vaginal gel subjects became pregnant (confirmed 2 weeks after embryotransfer) resulting in 4 term singleton deliveries and one set of twinsdelivering at 34 weeks. The full results of the pregnancies and livebirths are outlined in Table 7. Individual subject data is shown inTable 8. There were no biochemical pregnancies and no miscarriages inthe pregnant subjects. One of the pregnant intravaginal ring subjectswas discontinued from the study and switched to intramuscularprogesterone due to the bleeding pattern at 9 weeks of pregnancy (7weeks after embryo transfer).

TABLE 7 Biochemical Pregnancy, Clinical Pregnancy, and Live Birth RatesProgesterone Progesterone All Vaginal Ring Vaginal gel subjects Numberof fresh transfers 5 4 9 Number of embryos transferred 2 2 2 Biochemicalpregnancy [N (%)] 0 (0) 0 (0)  0 (0) Miscarriages [N (%)] 0 (0) 0 (0)  0(0) 8 week clinical pregnancy [N 4 (80) 1 (25) 5 (56) (%)] 12 weekclinical pregnancy [N 3* (60) 1 (25) 4* (44) (%)] Livebirth [N (%)] 3*(60) 1 (25) 4* (44) *One subject who became pregnant on the progesteroneVR was discontinued from the study at Week 9 of pregnancy due to vaginalbleeding. This subject was switched to IM progesterone and sustained thepregnancy until a live birth.

TABLE 8 Individual Subject Data Vaginal Cramping Vaginal bleedingPatient Study During spotting during No. Drug Pregnancy? Study? duringstudy? study? AEs reported 0103 VR Yes ET + 24 days ET + 24 days ET + 46days Nausea-intermittent; vomiting-intermittent; pelvic [switched toET + 43 days ET + 25 days cramping; vaginal spotting; vaginal bleeding;IM progesterone ET + 44 days ET + 26 days lower quadrant abdominalcramping due to vaginal bleeding; withdrawn from study; live birth] 0107VR No Light-headed; sore throat 0109 VR Yes (twins) ET + 9 days ET + 28days Vulvovaginal candidiasis; vaginal spotting (reports [Completed ET +20 days ET + 29 days progressively increased spotting toward time ofvaginal ring study] ET + 21 days change; cessation of spotting when newring is inserted); ET + 23-28 days gestational diabetes; mildhypertension; indigestion- ET + 30-41 days intermittent ET + 43-49 days0113 VR Yes (twins) Nausea-intermittent; indigestion-intermittent;diarrhea- [Completed intermittent study; no reported spotting/bleeding]0114 . VR Yes ET + 34 days ET + 34 days Vaginal Spotting;headache-intermittent; insomnia; pelvic ET + 38 dayscramps-intermittent; upper respiratory infection ET + 40-47 days 0102Gel No Upper respiratory infection 0106 Gel No - discontinued Sorethroat prior to embryo transfer 0115 Gel No ET + 2-9 Indigestion; coldsore - oral; pelvic cramping; pelvic days pressure; seasonal allergies;headache 0122 Gel No ET + 5-11 Headache, intermittent; lower abdominalcramping, days intermittent; upper respiratory infection 0125 Gel YesET + 41 days Intermittent nausea; left arm axilla, swollen glands; left[Completed axilla tenderness; left axilla, swollen glands; lower study]abdominal cramping; upper respiratory infection; vaginal spotting

The treatment emergent adverse events reported were similar among thetwo treatment groups, with a few exceptions. More adversevaginal/cervical findings and abdominal pain were reported in thevaginal gel group, and more vaginal bleeding/spotting was reported inthe vaginal ring treatment group. A summary of adverse events ispresented in Table 9.

TABLE 9 Adverse Events Occurring in >1 Subject Mock Cycle Vaginal RingVaginal Gel N = 10 N = 11 Any Adverse Event 10 9 Metrorrhagia 9 0Dysmenorrhea 1 1 Cervix erythema 1 1 Post-procedural 1 2 complicationAbdominal pain 0 3 Embryo Transfer Cycle Vaginal Ring Vaginal Gel N = 5N = 4 Any Adverse Event 5 3 Dyspepsia 2 1 Nausea 2 1 Lower abdominalpain 1 2 Metrorrhagia 3 1 Pelvic pain 2 1 Upper respiratory 1 2infection Headache 1 2

There were four subjects with adverse vaginal and/or cervical findingsin the mock cycle; 3 in the vaginal gel group and 1 in the intravaginalring group. The reported vaginal/cervical adverse events for the vaginalgel subjects included cervical face ulceration, erythema, externalvaginal irritation, grossly white findings, petechiae, uterine cervicalerosion, and vaginal erosion with superficial peeling. The single VRpatient with vaginal/cervical findings was reported to have erythema.

During the mock cycle, there was expected vaginal bleeding/spotting inboth treatment groups on the day of, and up to 2 days after, theendometrial biopsy (cycle days 25-27). No subjects in the vaginal gelgroup reported any vaginal bleeding/spotting from cycle days 28-31,while 9 out of 10 subjects did so in the intravaginal ring group(predominantly spotting). None of the subjects in the intravaginal ringgroup were discontinued due to bleeding/spotting during the mock cycle.Bleeding/spotting in the intravaginal ring group occurred primarily whenan intravaginal ring was used for longer than 7 days. The intravaginalring was designed as a 7-day ring, and the second intravaginal ring wasleft in place for 10 days in this study to evaluate the impact ofextending ring use beyond 7 days in case the ring was inadvertently leftin place for longer periods of time. The vaginal spotting for theintravaginal ring group occurred either on the day or day after theintravaginal ring would normally be changed (on or after cycle day 28).

Within the intravaginal ring treatment group, there were no reports ofirritation, discomfort, or issues with intercourse due to theintravaginal ring. In addition, there were no discontinuations due tothe ring falling out. There were no serious adverse events,discontinuations due to a treatment-related adverse event, or reports ofvaginal hemorrhage during the study.

In the embryo transfer cycle, none of the subjects had vaginal bleedingor spotting prior to the pregnancy test. Of the 5 subjects who achieveda pregnancy, 4 were using the intravaginal ring and 1 used the vaginalgel. Three of 4 had some vaginal bleeding or spotting during thepregnancy in the intravaginal ring treatment group, commencing on embryotransfer day 24-34 or at 6-7 weeks gestation. The spotting/bleedingstarted at the point in the pregnancy when serum progesterone levelswere increasing due to production by the trophoblasts. One of the 4pregnant intravaginal ring treatment subjects was switched tointramuscular progesterone due to an irregular bleeding pattern at 7weeks (after embryo transfer). Two remaining women had mild spotting at6-7 weeks which did not require any treatment. Vaginal gel subjects hadno vaginal bleeding or spotting before or after pregnancy tests duringthe treatment period. Of note, the twin pregnancy occurred in theintravaginal ring group and this subject experienced no spotting duringthe pregnancy.

Example 3

The intravaginal ring of Example 1 can be used in a study to compare theefficacy of the intravaginal ring to a progesterone vaginal gel forluteal phase supplementation for in vitro fertilization. This study willbe in women undergoing in vitro fertilization with fresh eggs. Multiplesites will randomize approximately 1300 eligible women in a 1:1 ratio toeither a progesterone intravaginal ring or a progesterone vaginal gelonce daily. Detailed past obstetrical history will be recorded,including gravidity, parity, previous abortions, and ectopicpregnancies.

The ovarian suppression/stimulation protocols will be a Lupron®(leuprolide acetate) down-regulation protocol with a combination of FSH(follicle stimulating hormone) and an LH-containing product forstimulation (luteinizing hormone). Suppression will take place duringthe cycle before the embryo transfer cycle. After suppression,stimulation will begin once down-regulation is achieved. The length ofstimulation will be dependent upon each patient, the site's standardprotocols, and/or the investigator's discretion. During stimulation, thepatient will be monitored to determine when to trigger ovulation for thepatient with hCG (Human Chorionic Gonadotropin). Egg retrieval willoccur approximately 35-37 hours after hCG administration and embryotransfer will occur 3 or 5 days after egg retrieval. A serum pregnancytest will be conducted 2 weeks after the egg retrieval. Those patientswith a βhCG <5 mIU will be discontinued from the study. Those patientswith a βhCG >5 mIU will continue dosing with progesterone through 12weeks of pregnancy, with an evaluation of clinical pregnancy rates at 8and 12 weeks of pregnancy. All pregnancies will be followed untilcompletion to determine live birth rates. The overall study durationwill be approximately 10 months for patients who become pregnant andgive birth.

In each case the patients will be administered either a progesteroneintravaginal ring of Example 1 or the progesterone vaginal gel. In eachcase the progesterone treatment will begin the day after egg retrievaland continue through week 12 of pregnancy (10 weeks post egg retrieval).

One half of the registered participants will be administered theintravaginal ring of Example 1, which will be changed on a weeklyschedule, whereby the intravaginal ring will deliver between about 10 mgof progesterone to about 30 mg of progesterone (in vivo release) to thepatient each day for about seven days. Similarly, for the patientsadministered progesterone vaginal gel, treatment will begin the dayafter egg retrieval and continue through week 12 of pregnancy (10 weekspost egg retrieval).

The co-primary objectives in this study are clinical pregnancy rate(i.e., visualization of a gestational sac with fetal heart motionpresent on ultrasound) at 8 weeks of pregnancy (6 weeks after eggretrieval) and at 12 weeks of pregnancy (10 weeks after egg retrieval)using the intravaginal ring of Example 1 or progesterone vaginal gel toprovide progesterone supplementation. In this study, pregnancy isdefined as beginning 2 weeks prior to egg retrieval. Secondaryobjectives include a study of live birth rate, cycle cancellation rate,rate of spontaneous abortion, rate of biochemical pregnancy, rate ofectopic pregnancy, and the safety and tolerability of the intravaginalring of Example 1.

CONCLUSION

All of the various embodiments or options described herein can becombined in any and all variations. While the invention has beenparticularly shown and described with reference to some embodimentsthereof, it will be understood by those skilled in the art that theyhave been presented by way of example only, and not limitation, andvarious changes in form and details can be made therein withoutdeparting from the spirit and scope of the invention. Thus, the breadthand scope of the present invention should not be limited by any of theabove described exemplary embodiments, but should be defined only inaccordance with the following claims and their equivalents.

All documents cited herein, including journal articles or abstracts,published or corresponding U.S. or foreign patent applications, issuedor foreign patents, or any other documents, are each entirelyincorporated by reference herein, including all data, tables, figures,and text presented in the cited documents.

What is claimed is:
 1. A method of manufacturing a monolithicintravaginal progesterone ring, comprising: (a) mixing progesterone, apolysiloxane elastomer composition, and a pharmaceutically acceptablehydrocarbon or glycerol esters of a fatty acid or pharmaceuticallyacceptable oil, to form a homogeneous mixture; (b) placing thehomogeneous mixture into a mold; and (c) curing the homogeneous mixturein the mold to form a monolithic intravaginal progesterone ringcomprising about 10% to about 30% by weight of the progesterone, about60% to about 80% by weight of polysiloxane elastomer, and about 1% toabout 8% by weight of the pharmaceutically acceptable hydrocarbon orglycerol esters of fatty acid or pharmaceutically acceptable oil,wherein the progesterone is homogeneously dispersed in the elastomer. 2.The method of claim 1, wherein the polysiloxane elastomer is adiorganopolysiloxane elastomer.
 3. The method of claim 2, wherein thediorganopolysiloxane elastomer is a dimethylpolysiloxane elastomer. 4.The method of claim 3, wherein the dimethylpolysiloxane elastomer isvinyl end blocked.
 5. The method of claim 3, wherein thedimethylpolysiloxane elastomer further comprises adimethylmethylhydrogen polysiloxane crosslink.
 6. The method of claim 1,wherein the polysiloxane elastomer composition comprises, as separatecomponents, (i) dimethylpolysiloxane vinyl end-blocked polymer,non-crystalline trimethylsilyl treated fumed silica, and a platinumsilicone complex and (ii) dimethylpolysiloxane vinyl end-blockedpolymer, non-crystalline trimethylsilyl treated fumed silica,dimethylmethylhydrogen polysiloxane, and 2-methyl-3-butyn-2-ol.
 7. Themethod of claim 6, wherein step (a) comprises: (a1) mixing a firstportion of the progesterone, the polysiloxane elastomer compositioncomponent (i), and a first portion of the pharmaceutically acceptablehydrocarbon or glycerol esters of fatty acid or pharmaceuticallyacceptable oil, to form a first homogenous mixture; (a2) mixing a secondportion of the progesterone, the polysiloxane elastomer compositioncomponent (ii), and a second portion of the pharmaceutically acceptablehydrocarbon or glycerol esters of fatty acid or pharmaceuticallyacceptable oil, to form a second homogenous mixture; and (a3) mixing thefirst homogenous mixture with the second homogenous mixture.
 8. Themethod of claim 1, wherein the pharmaceutically acceptable hydrocarbonor glycerol esters of fatty acid or pharmaceutically acceptable oil isselected from mineral oil, silicone oil, and combinations thereof. 9.The method of claim 1, wherein the pharmaceutically acceptablehydrocarbon or glycerol esters of fatty acid or pharmaceuticallyacceptable oil is mineral oil.
 10. The method of claim 1, wherein thepolysiloxane elastomer is a dimethylpolysiloxane elastomer, and whereinthe ratio of progesterone to dimethylpolysiloxane elastomer topharmaceutically acceptable hydrocarbon or glycerol esters of fatty acidin the ring is about 4:15:1.
 11. The method of claim 1, wherein step (b)comprises injecting the homogeneous mixture into the mold.
 12. Themethod of claim 1, wherein step (c) comprises curing at a temperature offrom about 60° C. to about 180° C.
 13. The method of claim 1, whereinstep (c) comprises curing at a temperature of from about 70° C. to about150° C.
 14. The method of claim 1, wherein step (c) comprises curing ata temperature of from about 80° C. to about 120° C.
 15. The method ofclaim 1, wherein the intravaginal ring comprises: (a) from about 15% toabout 25% by weight of the progesterone; (b) from about 70% to about 80%by weight of a dimethylpolysiloxane elastomer; and (c) from about 1% toabout 8% by weight of the pharmaceutically acceptable hydrocarbon orglycerol esters of a fatty acid or pharmaceutically acceptable oil.